Obesity is a complex medical condition characterized by excessive body fat accumulation that poses significant health risks. The causes of obesity are multifactorial and not fully understood, encompassing genetic, environmental, psychological, nutritional, and metabolic factors. These elements interact to disrupt biological mechanisms, leading to increased adipose tissue mass, altered distribution, and impaired function. This article explores the diverse causes of obesity, shedding light on their interconnections and their impact on individual and public health.
Energy imbalance: A fundamental driver
At its core, obesity arises from a prolonged positive energy balance, where calorie intake surpasses calorie expenditure. This imbalance leads to the accrual of body fat as the rate of macronutrient appearance exceeds its disappearance. While often attributed to overeating, the underlying causes of this energy surplus are not straightforward.
Modern lifestyles contribute significantly to this imbalance. Easy access to energy-dense, processed foods—often marketed aggressively—combined with decreased physical activity due to urbanization and sedentary behaviors, fosters an obesogenic environment. However, emerging studies question whether physical inactivity alone explains rising obesity rates. Instead, the cumulative effect of sustained energy surpluses promotes weight gain through adipocyte hypertrophy (enlargement) and, to a lesser extent, hyperplasia (increased cell number).
Genetic factors and heritability
Genetic predisposition plays a pivotal role in the development of obesity, with studies estimating that 40–70% of body weight variation is attributable to genetic factors. Genome-wide association studies have identified numerous genetic variants influencing food intake, metabolism, and energy expenditure. People with obesity often carry a higher burden of these susceptibility variants.
Rare genetic mutations, such as those affecting the leptin-melanocortin pathway, can profoundly alter eating behavior by increasing hunger and reducing satiety. Such mutations underscore the biological complexity of obesity, illustrating that eating behavior is both innate and shaped by environmental interactions. Polygenic risk scores, which aggregate the effects of multiple genetic variants, may one day predict individual obesity risk with greater precision.
Environmental and sociocultural influences
The modern environment is a significant contributor to obesity. Urbanization and technological advancements have reduced physical activity levels while increasing exposure to calorie-dense, palatable foods. Sociocultural factors, including eating habits and societal norms, further exacerbate this issue. Within the same environment, however, individual responses vary widely due to genetic predispositions and behavioral differences.
Additionally, environmental pollutants are suspected to influence obesity, though their mechanisms remain largely undefined. Research into these factors is ongoing and may provide insights into novel preventive measures.
Metabolic and hormonal factors
The human body is evolutionarily programmed to conserve energy as fat, an adaptation critical for survival during periods of food scarcity. When weight loss occurs due to calorie restriction, the body responds with mechanisms designed to restore lost weight. These include increased hunger and reduced energy expenditure, mediated by hormonal changes such as decreased leptin levels and altered gut hormone responses.
This biological defense of a set-point weight, whether healthy or excessive, complicates long-term weight management. The brain plays a central role, with regions such as the hypothalamus and nucleus of the solitary tract regulating hunger, satiety, and energy expenditure.
Pathophysiology of obesity
Obesity’s impact extends beyond adipose tissue to multiple organs, including the liver, skeletal muscles, and pancreas. Excess fat storage in non-adipose tissues—referred to as ectopic lipid accumulation—leads to metabolic dysfunctions such as insulin resistance and chronic inflammation.
Adipose tissue dysfunction
Adipose tissue expansion during weight gain is associated with hypoxia, inflammation, and reduced insulin sensitivity. Inflammatory cytokines such as TNFα and IL-6 exacerbate these effects, contributing to metabolic disorders.
Central nervous system dysregulation
Obesity involves complex interactions among brain regions that regulate energy balance. The hypothalamus, nucleus accumbens, and ventral tegmental area, among others, influence appetitive behavior and energy regulation. Dysfunctions in these neural circuits drive overeating and reduced energy expenditure.
Genetic and epigenetic contributions
The study of monogenic and polygenic obesity has enhanced understanding of the biological pathways influencing weight regulation. Syndromic forms of obesity, such as Prader–Willi syndrome, highlight the interplay between genetic and environmental factors. Epigenetic modifications, influenced by diet and lifestyle, further add to the complexity of obesity.
Insulin resistance and metabolic consequences
While not all individuals with obesity develop insulin resistance, the majority experience some degree of metabolic dysfunction. Insulin resistance is a precursor to conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Ectopic lipid accumulation and chronic inflammation contribute to this resistance, impairing glucose and lipid metabolism.
Gut microbiota and inflammation
Alterations in gut microbiota composition are increasingly recognized as contributors to obesity. People with obesity often have higher levels of certain bacterial strains, such as Proteobacteria and Firmicutes, which may influence energy extraction from food and promote inflammation. Increased gut permeability to bacterial products like lipopolysaccharides further perpetuates systemic inflammation.
Neural and behavioral insights
The reward and emotional centers of the brain, including the nucleus accumbens and amygdala, play a significant role in obesity. Changes in dopamine signaling can increase the preference for calorie-dense foods, while altered emotional responses may drive overeating. The prefrontal cortex, responsible for inhibitory control, often shows reduced activity in individuals with obesity, contributing to poor dietary choices.
Conclusion
Obesity is a multifaceted condition influenced by genetic, environmental, metabolic, and behavioral factors. Its complexity requires a comprehensive approach to prevention and management. Understanding the interplay of these factors offers opportunities for targeted interventions, including dietary modifications, physical activity, and emerging therapies addressing genetic and hormonal contributors.
References
- Rubino F, Cummings DE, Eckel RH, et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes Endocrinol 2025 (in press)
- Kountouras J, Zavos C, Vardaka E, et al. Helicobacter pylori and metabolic syndrome-related adipokines in nonalcoholic fatty liver disease pathophysiology. J Gastroenterol Hepatol 2024;39:1957-9.